Antipsychotics and Hyponatremia

Hyponatremia is a rare but serious complication of antipsychotic treatment, often linked to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). This condition, which lowers sodium levels in the blood, can result in confusion, seizures, or even death. Mazhar and colleagues investigated this risk using the FDA Adverse Event Reporting System (FAERS), analyzing over 138,000 reports involving antipsychotics. They found that about 1.1% of reports mentioned hyponatremia, with olanzapine most frequently implicated. Importantly, their pharmacodynamic modeling suggested that receptor activity—particularly dopamine D3 and serotonin 5-HT2A pathways—may explain why certain drugs are more strongly associated with this outcome.

The study showed that higher occupancy of dopamine D3 receptors increased the risk of hyponatremia, while strong serotonin 5-HT2A activity appeared protective. Drugs with unbalanced receptor profiles, such as amisulpride, sulpiride, and prochlorperazine, were more often linked to hyponatremia. In contrast, agents with either balanced D3/5-HT2A activity (e.g., risperidone, chlorpromazine, aripiprazole, paliperidone) or high 5-HT2A blockade were less frequently implicated. This provides a pharmacological explanation for the variable risk across different antipsychotics and highlights the complexity of predicting adverse effects based on receptor binding.

An updated systematic review of 11 observational studies reinforced these findings, though results varied widely, with incidence rates ranging from as low as 0.003% to as high as 86% depending on the population, sodium cutoff, and monitoring approach. Overall, typical antipsychotics carried a consistently higher risk than atypical agents. Still, hyponatremia was not confined to older drugs, underscoring the need for clinicians to remain vigilant. The review concluded that patient-specific risk factors, drug receptor profiles, and systematic monitoring of sodium levels should all guide prescribing decisions.

https://pmc.ncbi.nlm.nih.gov/articles/PMC8278799/pdf/pyab005.pdf